Hollow fiber membrane and method for manufacturing thereof

ABSTRACT

The present invention concerns a semipermeable hollow fiber membrane having an outer wall surface, an inner wall surface and an interior lumen extending along the length thereof and having the selective layer on the outer wall surface with a surface roughness below 10 nm. According to the invention the membrane has the smallest pore size on the outer wall surface, and has an outer wall surface which is smooth, continuous and homogeneous in a nanoscopic scale and four to five distinct layers of different pore size and density. Further the present invention concerns a prone:is for manufacturing thereof and the use thereof.

TECHNICAL FIELD

The present invention concerns a semi-permeable hollow fiber membranehaving an outer wall surface, an inner wall surface and an interiorlumen extending along the length thereof. More particular it relates toa membrane having the selective layer on the outer wall surface.

BACKGROUND OF THE INVENTION

Semi-permeable hollow fiber membranes are known in detail in, forexample. EP-A-0 568 045, EP-A-0 168 783, EP-B′0082 433, WO 86/00028, andEP 0 824 960. These membranes are manufactured from polymeric syntheticmaterials, they have asymmetric structure with high diffusivepermeability (clearance) and have water filtration capability withultrafiltration in the range of low flux to high flux. In EP-A-0 305787, a 3-layer structure membrane and filter with correspondingperformance, is disclosed.

The membranes according to prior art are well performing, but still havesome space for improvement and optimization.

One limiting feature of these membranes are that the fluid to befiltered is intended to flow in the interior lumen of the hollow fiberand the filtrate to go through the fiber wall from the lumen side to theouter wall side. In order not to have these filters to foul or clog, thedimensions of the hollow fiber, such as inner diameter, wall thicknessand so on, have to be big enough to allow a good and high flow withinthe hollow fiber lumen.

In DE 199 13 416 it is suggested to make the filtration from outside toinside, i.e., to have the selective layer on the outside.

However, when working with body fluids like blood it is of mostimportance that the membrane surface, which is intended to be brought incontact with the body fluid, is as smooth as possible, has low proteinadsorption, high biocompatibility, and a low thrombogenicity.

DESCRIPTION OF THE INVENTION

The present invention concerns a semipermeable hollow fiber membranehaving an outer wall surface, an inner wall surface and an interiorlumen extending along the length thereof and having the selective layeron the outer wall surface. According to the invention, the membrane hasthe smallest pore size on the outer wall surface, and has an outer wallsurface which is smooth, continuous and homogeneous in a nanoscopicscale, being virtually devoid of roughness with a roughness parameterR_(a) and R_(q) of not more than 10 nm, the roughness being measuredwith the use of atomic force microscope (AFM), and calculating theroughness parameters R_(a) and R_(q) using the following equations:

$R_{a} = {\frac{1}{N}{\sum\limits_{i = 1}^{N}{Z_{i}}}}$$R_{q} = \sqrt{\frac{1}{N}{\sum\limits_{i = 1}^{N}Z_{i}^{2}}}$

with N being the total number of data points and Z_(i) being the heightof a data point above the average picture level. With this smooth outersurface, the combination of the polymer system used and the membraneformation conditions, low thromboginicity of the membrane is achieved.The extremely smooth surface does inhibit haemolysis if used in directblood contact. Blood cells will not be ruptured during the contact withthe smooth surface. The smoothness further reduces the interaction withproteins and the adsorption of proteins on the outer surface of thehollow fiber membrane.

In one embodiment the hollow fiber membrane wall has at least fourlayers with different pore sizes and mass densities, and wherein thelayer positioned closest to the middle of the membrane wall has smallerpore size and higher mass density than the two layers directly adjacenton both sides, inner and outer, of this layer. With this structure,physical stability of the membrane is maintained even though themembrane has a small inner diameter and a small wall thickness. Itfurther allows for tailoring the separation characteristics, i.e.cut-off and hydraulic permeability, by changing the structural densityand pore size of the outer layer and the middle layer.

In another embodiment the hollow fiber membrane wall has four layerswith different pore sizes and mass densities. A first layer, at theouter wall surface, has the smallest pore size and the highest massdensity. A second layer, adjacent the first layer and placed on theinside facing side of the first layer, has larger pore size and lowermass density than the first layer. A third layer, adjacent the secondlayer and placed on the inside facing side of the second layer, hassmaller pore size and higher mass density than the second layer, butlarger pore size and lower mass density than the first layer. A fourthlayer, at the inner wall surface and adjacent the third layer and placedon the inside facing side of the third layer, has larger pore size andlower mass density than the first, second and third layer. With thisstructure the degree of openness on the inner lumen side of the hollowfiber can be increased, which gives the possibility to increasediffusive transport properties if required. Also vortex like fluid flowcan be achieved directly on the inner lumen side, which is advantageousfor the mass transport phenomenon.

In an additional embodiment the hollow fiber membrane wall has fivelayers with different pore sizes and mass densities. A first layer, atthe outer wall surface, has the smallest pore size and the highest massdensity. A second layer, adjacent the first layer and placed on theinside facing side of the first layer, has larger pore size and lowermass density than the first layer. A third layer, adjacent the secondlayer and placed on the inside facing side of the second layer, hassmaller pore size and higher mass density than the second layer, butlarger pore size and lower mass density than the first layer. A fourthlayer, adjacent the third layer and placed on the inside facing side ofthe third layer, has larger pore size and lower mass density than thefirst, second and third layer. A fifth layer, at the inner wall surfaceand adjacent the fourth layer and placed on the inside facing side ofthe fourth layer, has larger pore size and lower mass density than thefirst, second, third, and fourth layer. With this structure the degreeof openness on the inner lumen side of the hollow fiber can beincreased, which gives the possibility to increase diffusive transportproperties if required. Also vortex like fluid flow can be achieveddirectly on the inner lumen side, which is advantageous for the masstransport phenomenon.

In another embodiment the hollow fiber membrane wall has five layerswith different pore sizes and mass densities. A first layer, at theouter wall surface, has the smallest pore size and the highest massdensity. A second layer, adjacent the first layer and placed on theinside facing side of the first layer, has larger pore size and lowermass density than the first layer. A third layer, adjacent the secondlayer and placed on the inside facing side of the second layer, hassmaller pore size and higher mass density than the second layer, butlarger pore size and lower mass density than the first layer. A fourthlayer, adjacent the third layer and placed on the inside facing side ofthe third layer, has larger pore size and lower mass density than thefirst, second and third layers. A fifth layer, at the inner wall surfaceand adjacent the fourth layer and placed on the inside facing side ofthe fourth layer, has smaller pore size and higher mass density than thefourth layer. With this structure the inner surface can also be equippedwith a smooth inner surface, which is required if two fluid systems,having high fouling potential, are passed on the inside and the outside,respectively, of the hollow fiber membrane. The smooth inner surfacereduces the risk of haemolysis (in the case of blood contact) and therisk of fouling and the adsorption of substances on the surface. Inaddition to this the diffusive and convective transport properties canbe adjusted by fine tuning the morphology, i.e. structure, of the innerlayer. Due to this layer structure the mechanical properties can befurther increased.

In a further embodiment the hollow fiber membrane has a hydraulicpermeability within the range of 1×10⁻⁴-100×10⁻⁴[cm³/cm²×bar×s],preferably within the range of 1×10⁻⁴ to 70×10⁻⁴ [cm³/cm²×bar×s], andmost preferably within the range of 1×10⁻⁴ to 27×10⁻⁴ [cm³/cm²×bar×s].With this hydraulic permeability the convective transport through themembrane wall is minimized at the same time having high diffusivetransport in a broad range with respect to the molecular size (up to100.000 Dalton depending on the fluid and measurement condition) orshape of the molecule.

In another embodiment the hollow fiber membrane comprises a polymercomposition comprising polysulphone (PSU), polyethersulphone (PES) orpolyarylethersulphone (PAES); and polyvinylpyrrolidone (PVP).

In even another embodiment the polyvinylpyrrolidone (PVP) in themembrane comprises a blend of at least two homo-polymers ofpolyvinylpyrrolidone (PVP), and wherein one of the homo-polymers has anaverage relative molecular weight within the range of 10.000 g/mole to100.000 g/mole, preferably within the range of 30.000 g/mole to 60.000g/mole (=low molecular weight PVP), and another one of the homo-polymershas an average relative molecular weight within the range of 500.000g/mole to 2.000,000 g/mole, preferably within the range of 800.000g/mole to 2.000.000 g/mole (=high molecular weight PVP).

In one embodiment the hollow fiber membrane has an inner diameter withinthe range of 50 to 2000 μm, preferably within the range of 104 to 1464μm.

In one embodiment the hollow fiber membrane has a wall thickness withinthe range of 10 to 200 ∞m, preferably within the range of 22 to 155 μm.

In another embodiment the hollow fiber membrane has an effectivediffusion coefficient through the membrane for urea (60 g/mole) of4×10⁻⁶ to 15×10⁻⁶ cm²/s.

Further, the present invention concerns a process for manufacturing of asemipermeable hollow fiber membrane, comprising the steps of extruding apolymer solution through an outer ring slit of a hollow fiber spinningnozzle, simultaneously extruding a bore liquid through the inner bore ofthe hollow fiber spinning nozzle, into a precipitation bath. Accordingto the invention the polymer solution contains 10-20 wt.-% ofpolysulphone (PSU), polyethersulphone (PES) or polyarylethersulphone(PAES), 2-15 wt.-% polyvinylpyrrolidone (PVP) and a solvent, the boreliquid contains 50-75 wt.-% of a solvent and 25-50 wt.-% of water, theprecipitation bath contains 50-70 wt.-% of a solvent and 30-50 wt.-% ofwater and has a temperature within the range of 22-31° C., and thedistance between the discharge outlet of the hollow fiber spinningnozzle and the surface of the precipitation bath is within the range of0-10 cm.

In one embodiment of the process according to the invention, theprecipitation bath contains 52-69 wt.-% of a solvent and 31-48 wt.-% ofwater.

In another embodiment of the process according to the invention, thesolvent in the polymer solution, the bore liquid and the precipitationbath is chosen from N-methylpyrrolidone, N-ethylpyrrolidone,N-octylpyrrolidone, dimethylacetamide, dimethylformamide, dimethylsulphoxide, gamma-butyrolactone or mixtures thereof.

In even another embodiment of the process according to the invention,the solvent in the polymer solution, the bore liquid and theprecipitation bath is chosen from is N-methylpyrrolidone,N-ethylpyrrolidone, N-octylpyrrolidone or mixtures thereof, preferablyN-methylpyrrolidone.

In a further embodiment of the process according to the invention, thepolymer solution contains 17-18 wt.-% of polysulphone (PSU),polyethersulphone (PES) or polyarylethersulphone (PAES), 8-11.25 wt.-%of polyvinylpyrrolidone (PVP) and 70-75 wt.-% of a solvent.

In another embodiment of the process according to the invention, thepolyvinylpyrrolidone (PVP) in the polymer solution comprises a blend ofat least two homo-polymers of polyvinylpyrrolidone (PVP), and whereinone of the homo-polymers has an average relative molecular weight withinthe range of 10.000 g/mole to 100.000 g/mole, preferably within therange of 30.000 g/mole to 60.000 g/mole (=low molecular weight PVP), andanother one of the homo-polymers has an average relative molecularweight within the range of 500.000 g/mole to 2.000.000 g/mole,preferably within the range of 800,000 g/mole to 2.000.000 g/mole (=highmolecular weight PVP).

In another embodiment of the process according to the invention, thepolymer solution, based on the total weight of the polymer solution,contains the low molecular weight PVP in an amount of 1-10 wt.-%,preferably in an amount of 5-8 wt.-%, and the high molecular weight PVPin an amount of 1-5 wt.-%, preferably in an amount of 3-3.25 wt.-%.Ineven another embodiment of the process according to the invention, theprecipitation bath has a temperature within the range of 22-27° C.

In a further embodiment of the process according to the invention, thehollow fiber spinning nozzle is held at a temperature within the rangeof 40-70° C., preferably within the range of 54-60° C.

In one embodiment of the process according to the invention, thedistance between the discharge outlet of the hollow fiber spinningnozzle and the surface of the precipitation bath is within the range of0-4 cm. The discharge outlet is the outlet where the polymer solutionenters out of the spinning nozzle.

In another embodiment of the process according to the invention, thespinning speed of the hollow fiber membrane is 5-70 m/min, preferably7.5-45 m/min.

In another embodiment of the process according to the invention thepolymer solution has a viscosity, measured at room temperature, within arange of 10 000 to 100 000 mPa×s, preferably within the range of 21 500to 77 000 mPa×s.

The present invention further concerns the use of the hollow fibermembrane according to above, or prepared by the process according toabove in hemodialysis, as a sensor membrane for direct blood contact, asa sensor membrane in water applications, such as waste waterapplications, and delivery membrane in biological processes.

There are at least three potential applications for this type ofmembrane. In all potential applications the outside of the membrane isin contact with a fluid that has the potential to foul the membrane.However, there might be additional applications were this is not thecase.

Commercial membranes, e.g. having the selective layer on the inside andpores in the μm range on the outside, will either block or lead tohaemolysis in blood based applications if blood where brought in contactwith the outer wall surface. In the following applications the membranedescribed in this patent application shows clear advantages.

The membrane according to the present invention could be used ashemodialysis membrane where the blood is in contact with the outside ofthe membrane. For this application, the outside of the membrane shouldhave an equal pore size, diffusion coefficient, and material compositionand roughness as the inside of commercial dialysis membranes, which havethe blood contacting surface on the inside of the dialysis membrane.Depending on the pore size, the transport kinetics through the membranemight be dominated by diffusion. If the pore sizes were increased andthe low roughness were kept, the transport kinetics could be based on acombination of diffusion and convection. The smooth outer surface of themembrane is required to not allow blood cells and high molecular weightproteins to enter the porous membrane structure. If blood cells and highmolecular weight proteins where to enter the porous membrane structure,this could lead to rupture of the blood cells and formation of proteinlayers in the structure. Both effects are not acceptable in thisapplication.

The membrane according to the present invention could also be used as asensor membrane (micro-dialysis) for direct blood applications. Ifmicro-dialysis in direct blood applications is performed, fouling of themembrane is a severe problem. Cells can enter the outside of themembrane if pores exceed a few μm in diameter. At the same time highmolecular weight proteins can enter the porous structure of themembrane. This leads to pore blocking and the generation of a proteinlayer inside the porous membrane structure of the wall. In an extremecase, the outer surface of the membrane could lead to clot formation.Therefore a highly biocompatible surface is required for this type ofapplication. The same counts for the application as dialysis membrane.

The membrane according to the present invention could further be used asa sensor membrane in (waste) water applications. In these applicationsit is important to analyze the ion concentration to control thecomposition of waste water or analyze the content of ions in watersamples. To simplify the analysis, only the ions should pass through themembrane and not high molecular weight substances. For this applicationthe transport should be based mainly on diffusion. A high amount ofconvective transport would dilute the analysis system. At the same timethe transport of the ions should be stable over days, weeks or month.Therefore the outside of the membrane should have low foulingproperties. This again is achieved by a combination of materialproperties, pore size and surface roughness.

The membrane according to the present invention could further be used asa delivery membrane in biological processes. In fermenter systems itmight be necessary to control the amount of a fluid or substance that isadded to the process over time. To allow an extremely homogeneousdilution of such substances a hollow fiber membrane hanging in a stirredtank reactor having a smooth outer surface and tailor made diffusioncharacteristics is of use.

This is of course only some possible applications of the membraneaccording to the present invention. There might be a vast number ofother applications out there, which would benefit from this type oftailor made membrane. In general, the advantages and properties of themembrane according to the invention can be summarized as follows:

-   -   Most narrow pore size on the outside of the membrane    -   Smooth surface on the outside    -   Low protein adsorption properties of the outside structure    -   Highly biocompatible surface of the outside structure (i.e. low        thrombogenicity)    -   Hydraulic permeability between 1×10⁻⁴ and 100×10⁻⁴ cm³/(cm² bar        sec)    -   Hydrophilic—spontaneous wetting membrane    -   Sponge-like structure    -   Inner diameter between 50 and 2000 μm    -   Wall thickness between 10 and 200 μm    -   Transport based on diffusion or on diffusion and convection    -   Mechanical stability    -   Thin selective layer allowing high mass transfer rates

To allow manufacturing of skin outside membranes by a diffusion inducedphase separation (DIPS) procedure a number of criteria have to befulfilled.

The porous structure behind the “selective” outer surface in directionto the lumen side has larger pores up to several μm. The porousstructure is gained by a slow phase separation process. To allow a slowphase separation process the amount of a solvent (solvent for thepolymer) has to be sufficient high. However, high concentration of asolvent in the bore liquid (could also be called the center fluid, whichis introduced in the bore or center of the hollow fiber during theprecipitation procedure) and the precipitation bath creates instabilityof the fiber. This makes it difficult to get stable fibers into theprecipitation bath and out of this bath. The challenge is to adjust thesolvent concentration during the precipitation procedure (in the centerand the precipitation bath) and the precipitation bath temperature insuch a way that it allows the creation of a membrane that has smallerpores on the outer surface than on the inner surface in addition with avery smooth outer surface for good biocompatibility.

The challenge is to find a production window that allows to adjust (i)sufficiently high concentration of solvent in the center to generate avery open structure that allows a small mass transfer resistance overthe membrane, (ii) a solvent concentration in the precipitation bath toget a smooth surface structure on the outside of the membrane with poresin the selective layer within the range of 1 to 10 nm in combinationwith a highly biocompatible surface (material composition, roughness andso on), and (iii) stable spinning conditions. The major processparameters on the spinning machine are:

-   -   polymer composition in the polymer solution    -   temperature of the spinning nozzle    -   design of the spinning nozzle    -   distance between spinning nozzle and precipitation bath    -   conditions in the atmosphere between spinning nozzle and        precipitation bath    -   dimensions of the hollow fiber    -   composition of the bore liquid    -   composition of the precipitation bath    -   temperature of the precipitation bath    -   spinning speed    -   time/distance the fiber is moving through the precipitation bath

The mentioned parameters are not complete. This is just to give anindication about the process parameters and the complexity.

When the polymer solution has been prepared, see e.g. Example 1 for thisinformation, the polymer solution is pumped through a spinning nozzleand the liquid hollow fiber is formed. The solvent concentration in thebore liquid leads to an open structure at the inner side of themembrane. The distance between the spinning nozzle and the precipitationbath, the concentration range of solvent in the precipitation bath andthe time and the distance the fiber is moving through the precipitationbath, leads to a very smooth surface structure on the outer surface. Inone embodiment of the process according to the invention, the time inthe precipitation bath is between 2 and 60 seconds.

The smallest pores are at the outer side of the membrane. The overallstructure and the pores at the inside of the membrane are much larger.The selective layer at the outside is intended for direct blood contact.The challenge is to adjust the spinning conditions to fulfill theprofile of the membrane, i.e. biocompatibility, a small mass transferresistance and so forth.

The temperature and the solvent concentration in the precipitation bathinteract strongly with each other. Increasing the temperature wouldallow to decrease the solvent concentration, resulting in the samestructure of morphology, pore size and hydraulic permeability. However,there are technical limits when increasing the temperature of theprecipitation bath.

The biocompatibility of the membrane is proven to be very good based onthe comparable characteristics of the selective layer of a regulardialysis membrane (inside) and the morphology and characteristics of theoutside layer of this special membrane. However, to even increase thisfurther it might be of value to functionalize the outer surface of themembrane. One option could be to covalently bind heparin to the surface.To allow covalent binding of heparin, the membrane could be treated withplasma ignition together with a precursor gas containing functionalgroups as disclosed in WO2006/006918 or in WO03/090910.

BRIEF DESCRIPTION OF THE DRAWING(S)

FIG. 1 a to 1 d show a hollow fiber membrane according to one embodimentof the present invention, produced according to example 1 below.

FIG. 2 a to 2 d show a hollow fiber membrane according to anotherembodiment of the present invention, produced according to example 2below.

FIG. 3 a to 3 d show a hollow fiber membrane according to anotherembodiment of the present invention, produced according to example 3below.

FIG. 4 a to 4 d show a hollow fiber membrane according to anotherembodiment of the present invention, produced according to example 4below.

FIG. 5 a to 5 d show a hollow fiber membrane according to anotherembodiment of the present invention, produced according to example 5below.

FIG. 6 a to 6 d show a comparative example of a hollow fiber membrane,produced according to the comparative example below.

MATERIAL AND METHODS AFM Analysis:

The AFM studies have been preformed using an Atomic Force Microscopefrom Digital Instruments/Veeco, Type: NanoScope IIIa Multi Mode. Tominimize the interaction between the measurement probe and the membranematerial/membrane surface, the data is obtained using the Tapping Mode.This allows to the generation of stable pictures/data from the surfacetopography of the outer membrane surface. Due to the extremely smoothsurface and the small pores of the outer surface of the hollow fibermembranes special probes having a small radius at the tip of the probe,are used. The tips used for the measurement in this application (fromNanosensors, Type SSS-NCH (Super Sharp Silicon)) had a typical tip angleof R≈2 nm. Some samples, having a slightly higher surface roughness,have been measured using a NCH (Nanosensors) tip with a typical tipangle of R≈10 nm. The samples measured have a size of 2×2 μm or a sizeof 5×5 μm.

To perform the measurement the membrane samples have been placed on afiat substrate using double-sided adhesive tape. Surface areas of 5 μm×5μm, 2 μm×2 μm, and 1 μm×1 μm have been characterised using the atomicforce microscope (AFM). Every single data set of the different picturesshown are analysed, calculating different roughness parameter (R_(a),R_(q)) using the following equations:

$R_{q} = \sqrt{\frac{1}{N}{\sum\limits_{i = 1}^{N}Z_{i}^{2}}}$$R_{a} = {\frac{1}{N}{\sum\limits_{i = 1}^{N}{Z_{i}}}}$

with N=Total number of data points

and Z_(i)=Height of a data point above the average picture level

Membrane Bundle Preparation:

Preparation of Hand Bundles:

The preparation of the membrane bundle after the spinning process isnecessary in order to prepare the fiber bundle in an adequate way forsucceeding performance tests. The first process step is to cut the fiberbundles to a defined length of 23 cm. The next process step consists ofclosing the ends of the fibers. An optical control ensures that allfiber ends are closed. Then, the ends of the fiber bundle aretransferred into a potting cap. The potting cap is fixed mechanicallyand a potting tube is put over the potting caps. Afterwards, the pottingis done with polyurethane. After the potting it has to be ensured thatthe polyurethane can harden for at least one day. In the next processstep, the potted membrane bundle is cut to a defined length. The lastprocess step consists of an optic control of the fiber bundle. Duringthis process step, the following points are controlled:

-   -   Quality of the cut (is the cut smooth or are there any damages        created by the knife);    -   Quality of the potting (is the number of open fibers of the        spinning process reduced by fibers that are potted, or are there        any visible voids where there is no polyurethane).

After the optical control, the membrane bundles are stored dry beforethey are used for the different performance tests.

Preparation of Mini-Modules:

Mini-modules [=fiber bundles in a housing] are prepared with relatedprocess steps. The mini-modules are needed to ensure a protection of thefibers and a very clean manufacturing method as the biocompatibilitytests are carried out with human plasma. The manufacturing of themini-modules differs in the following points:

-   -   The fiber bundle is cut to a defined length of 20 cm;    -   the fiber bundle is transferred into the housing before closing        the fiber ends; and    -   the mini-module is put into a vacuum drying oven over night        before the potting process.

Preparation of Filters:

The filter (=dialyzer) has around 8.000-10.000 fibers with an effectivesurface area of 0.5 to 0.6 m². A filter is characterized by acylindrical housing with two connectors for the dialyzing fluid andapplied caps on both sides, each with one centred blood connector. Themanufacturing process (after winding) can be split up into the followingmain steps:

-   -   The cut (length of 20 cm) bundles are transferred i to the        housing with a special bundle claw;    -   both ends of the bundles are closed ;    -   potting the fibers into the housing with Polyurethane (PUR);        cutting of the ends to open the fibers, wherein a smooth surface        is required;    -   visual control of the ends for closed fibers or imperfections in        the PUR block; and    -   gluing of the caps with he blood connectors.

Hydraulic Permeability (Lp) of Hand Bundles and Mini-Modules:

From Inside lo Outside (Hand Bundles):

The hydraulic permeability of a membrane bundle is determined bypressing an exact defined volume of water under pressure through themembrane bundle, which is closed on one side of the bundle and measuringthe required time. The hydraulic permeability can be calculated with thedetermined time, the effective membrane surface area, the appliedpressure and the volume of water, which is pressed through the membrane.The effective membrane surface area can be calculated by the number offibers, the fiber length and the inner diameter of the fiber. Themembrane bundle has to be wetted thirty minutes before the test isperformed. Therefore, the membrane bundle is put in a box containing 500ml of ultrapure water. After 30 minutes, the membrane bundle istransferred into the testing system. The testing system consists of awater bath that has a temperature of 37° C. and a device where themembrane bundle can be implemented mechanically. The filling height ofthe water bath has to ensure that the membrane bundle is locatedunderneath the water surface in the designated device. To avoid that aleakage of the membrane leads to a wrong test result, an integrity testof the membrane bundle and the test system has to be carried out inadvance. The integrity test is performed by pressing air through themembrane bundle which is dosed on one side of the bundle. Air bubblesindicate a leakage of the membrane bundle or the test device. It has tobe checked if the leakage can be associated with the wrongimplementation of the membrane bundle in the test device, or if a realmembrane leakage is present. The membrane bundle has to be discarded, ifa leakage of the membrane is detected. The applied pressure of theintegrity test has to be at least the same value as the applied pressureduring the determination of the hydraulic permeability, in order toensure that no leakage can occur during the measurement of the hydraulicpermeability, because of a too high applied pressure.

From Outside to Inside (Minimodules):

The measurements were carried out following the same measuring principleas mentioned in the measurement from inside to outside.

Hydraulic Permeability (Lp) of Filters:

From Inside to Outside:

In difference to testing procedure at hand bundles, the hydraulicpermeability of a filter is determined by flowing an exactly definedvolume of water through the membrane, and the trans membrane pressure ismeasured. Before starting the measurement, the filter has to be totallyfilled (inside the membrane and the compartment between the housing andthe membranes) with the testing fluid. Air is thereby removed by easyknocking. The testing fluid, pure water with a sodium chlorideconcentration of 0.9%, is set to a temperature of 38° C. and is therebypumped to the blood inlet of the filter, whereby the exit bloodconnector and the entrance of the dialyzed connection are closed. Themeasurement takes 5 minutes and average values for the pressures arecalculated. The calculation of the hydraulic permeability is equal tothe description for the hand bundles/mini modules.

From Outside to Inside:

The principle of the measurement is the same as for measuring frominside to outside, except of filtration of the pure water in backwarddirection. In this, the fluid is pumped to the dialysate inlet and theblood inlet as well as the dialysate exit is closed.

Permeability Tests/Diffusion Experiment of Hand Bundles:

Diffusion experiments with isotonic chloride solution are carried out todetermine the diffusion properties of a membrane. A hand bundle is putin a measuring cell. The measuring cell allows to pass the chloridesolution at the inside of the hollow fiber. Additionally, the measuringcell is filled completely with water, and a high cross flow of distilledwater is set to carry away the chloride ions that pass the membranecross section from the inside of the hollow fiber to the outside. Byadjusting the pressure ratios correctly, a zero filtration is aimed forso that only the diffusion properties of the membrane are determined (byachieving the maximum concentration gradient of chloride between theinside of the hollow fiber and the surrounding of the hollow fiber) andnot a combination of diffusive and convective properties. A sample fromthe pool is taken at the beginning of the measurement and a sample ofthe retentate is taken after 10 and 20 minutes. The samples are thentitrated with a silver nitrate solution to determine the chlorideconcentration. With the obtained chloride concentrations, the effectivemembrane surface area and the flow conditions, the chloride permeabilitycan be calculated. The same set-up can be used to analyse thepermeability of other substances/proteins. Tests have been performedusing urea as test substance. The concentration of urea in the differentsolutions is quantified using standard methods. The method used todetermine the permeability (P_(m)) is described by Elias Klein et.al.

E. Klein, F. F. Holland, A. Donnaud, A. Lebeouf, K. Eberle, “Diffusiveand hydraulic permeabilities of commercially available hemodialysisfilms and hollow fibers”, Journal of Membrane Science, 2 (1977) 349-364.

E. Klein, F. F. Holland, A. Lebeouf, A. Donnaud J. K. Smith, “Transportand mechanical properties of hemodialysis hollow fibers”, Journal ofMembrane Science, 1 (1976) 371-396.

Further Literature: References in the articles of E. Klein mentioned.

The effective diffusion coefficient (D_(Meff)) of a certain substance(substance, ion, or protein) is related to the membrane diffusivepermeability (P_(m)) of this substance by D_(Meff)=P_(m)×Δz, where Δz isthe diffusive distance (wall thickness of the membrane).

Viscosity Measurements:

The term “viscosity” in respect of the polymer solution of the presentinvention means the dynamic viscosity, if not otherwise indicated. Theunit of the dynamic viscosity of the polymer solution is given inCentipoise (cp) or mPa×s. To measure the viscosity of the polymersolution, a commercial rheometer from Rhemoetic Scientific Ltd. (SR2000) was used. The polymer solution is placed between twotemperature-controlled plates. The measurement is performed at 22° C.All other measurement condition are according to the manufacturer'sinstructions.

EXAMPLES Example 1

A polymer solution is prepared by dissolving polyethersulphone (BASFUltrason 6020) and polyvinylpyrrolidone (PVP) (BASF K30 and K85) inN-methylpyrrolidone (NMP). The weight fraction of the differentcomponents in the polymer spinning solution was: PES-PVP K85-PVPK30-NMP: 18-3,25-8-70,75. The viscosity of the polymer solution was53560 mPa×s.

To prepare the solution NMP is first filled into a three neck-flask withfinger-paddle agitator in the center neck. The PVP is added to the NMPand is stirred at 50° C. until a homogeneous clear solution is prepared.Finally, the polyethersulphone (PES) is added. The mixture is stirred at50° C. until a clear high viscous solution is obtained. The warmsolution is cooled down to 20° C. and degassed. To fully degas thesolution, the highly viscous polymer solution is transferred into astable stainless steel container. Thereafter the container is closedtightly and vacuum is applied to the container. The solution is degassedat 50 mmHg for 6 hours. During this degassing procedure the container isrotated to create a larger surface and thinner film thickness of thepolymer solution in the container, to improve the degassing procedure.

A membrane is formed by heating the polymer solution to 50° C. andpassing the solution through a spinning nozzle (also called spinning dieor spinneret). As bore liquid, a water and NMP mixture containing 42wt.-% water and 58 wt.-% NMP is used. The temperature of the spinningnozzle is 55° C. The hollow fiber membrane is formed at a spinning speedof 10 m/min. The liquid capillary leaving the spinning nozzle is passedinto a NMP/water bath (NMP concentration is 52%) having a temperature of26° C. The length of the distance between the spinning nozzle and theprecipitation bath is 4 cm. The formed hollow fiber membrane is guidedthrough a water bath having a temperature of 65° C. The wet hollow fibermembrane has an inner diameter of 1012 μm, an outer diameter of 1152 μmand a fully asymmetric membrane structure. The active separation layerof the membrane is at the outer wall surface. The active separationlayer is defined as the layer with the smallest pores. The hydraulicpermeability (Lp value) of the membrane was measured from inside tooutside in a hand bundle, using the methods described earlier. Themembrane showed a hydraulic permeability of 3.5×10⁻⁴ cm³/(cm² bar sec).

In FIG. 1 a, a scanning electron micrograph of the cross-section of thehollow fiber membrane is shown. In FIG. 1 b a close up of thecross-section of the hollow fiber wall is shown and, as is evident fromthe picture, the wall has an asymmetric structure and the overallstructure is a sponge-like structure. There are five different layerswithin the hollow fiber wall, and these different layers have beenmarked up, and as could be seen from the picture, the different layershave different pore sizes and different mass densities. The first layeris the outer selective layer and this layer has the smallest pores andthe highest mass density. The second layer has larger pores and lowermass density than the first layer. The third layer has smaller pores andhigher mass density than the second layer, but larger pores and lowermass density than the first layer. The fourth layer has larger pores andlower mass density than all of first, second and third layer. The fifthlayer has smaller pores and higher mass density than the fourth layer.In FIG. 1 c the inner wall surface is shown, and in FIG. 1 d the outerwall surface is shown and the outer wall surface is very smooth and havesmooth pores.

The roughness of the outer wall surface was measured and calculated asdisclosed above with a probe having a tip angle of R≈2 nm. For a sampleof the size 2×2 μm, the roughness parameters were R_(a) 4.9 nm and R_(q)6.3 nm, and for a sample of the size 5×5 μm, the roughness parameterswere R_(a) 7.9 nm and R_(q) 10.0 nm.

Example 2

The second example has been carried out with the identical compositionof the polymer solution as in Example 1. The viscosity of the polymersolution was 60200 mPa×s.

The polymer preparation procedure was kept as described in Example 1.The membrane formation procedure was changed for the following points:

-   -   Temperature of the spinning nozzle: 54° C.    -   Spinning velocity: 7.5 m/min    -   Distance between the spinning nozzle and the precipitation bath:        2.5 cm    -   Temperature of the precipitation bath: 27° C.

The remaining process steps are kept as in example 1. The wet hollowfiber membrane has an inner diameter of 1464 μm, an outer diameter of1592 μm and a fully asymmetric membrane structure. The active separationlayer of the membrane is at the outer wall surface. The activeseparation layer is defined as the layer with the smallest pores. Thehydraulic permeability (Lp value) of the membrane is measured frominside to outside in a hand bundle, using the methods described earlier.The membrane showed a hydraulic permeability of 3.4 ×10⁻⁴ cm³/(cm² barsec).

In FIG. 2 a, a scanning electron micrograph of the cross-section of thehollow fiber membrane is shown. In FIG. 2 b a close up of thecross-section of the hollow fiber wall is shown and, as is evident fromthe picture, the wall has an asymmetric structure and the overallstructure is a sponge like structure. There are five different layerswithin the hollow fiber wall, and these different layers have beenmarked up, and as could be seen from the picture the different layershave different pore sizes and different mass densities. The first layeris the outer selective layer and this layer has the smallest pores andthe highest mass density. The second layer has larger pores and lowermass density than the first layer. The third layer has smaller pores andhigher mass density than the second layer, but has larger pores andlower mass density than the first layer. The fourth layer has largerpores and lower mass density than all of the first, second and thirdlayers. The fifth layer has smaller pores and higher mass density thanthe fourth layer. In FIG. 2 c the inner wall surface is shown, and inFIG. 2 d the outer wall surface is shown and the outer wall surface isvery smooth and have smooth pores.

The roughness of the outer wall surface was measured and calculated asdisclosed above with a probe having a tip angle of R≈2 nm. For a sampleof the size 2×2 μm, the roughness parameters were R_(a) 1.9 nm and R_(q)2.4 nm, and for a sample of the size 5×5 μm, the roughness parameterswere R_(a) 2.8 nm and R_(q) 3.6 nm.

Example 3

The third example has been carried out with the identical composition ofthe polymer solution as in Example 1. The viscosity of the polymersolution was 59300 mPa×s.

The polymer preparation procedure was kept as described in Example 1.The membrane formation procedure was changed for the following points:

-   -   Bore liquid (H₂O: NMP) 38 wt.-% : 62 wt.-%    -   Concentration of NMP in the precipitation bath: 64 wt.-%    -   Distance between the spinning nozzle and the precipitation        bath:3 cm    -   Temperature of the precipitation bath: 22° C.

The remaining process steps are kept as in Example 1. The onlydifference is that the fiber had different dimensions. The hollow fibermembrane has an inner diameter of 203 μm, an outer diameter of 281 μmand a fully asymmetric membrane structure. The active separation layerof the membrane is at the outer wall surface. The active separationlayer is defined as the layer with the smallest pores. The hydraulicpermeability (Lp value) of the membrane is measured from inside tooutside in a hand bundle and from outside to inside in a mini-moduleusing the methods described earlier. The membrane showed a hydraulicpermeability of 6.7×10⁻⁴ cm³/(cm² bar sec) when measured from inside tooutside and 6.7×10⁻⁴ cm³/(cm² bar sec) when measured from outside toinside.

In FIG. 3 a, a scanning electron micrograph of he cross-section of thehollow fiber membrane is shown. In FIG. 3 b a close-up of thecross-section of the hollow fiber wall is shown and, as is evident fromthe picture, the wall has an asymmetric structure and the overallstructure is a sponge like structure. There are four different layerswithin the hollow fiber wall, and these different layers have beenmarked up, and as could be seen from the picture, the different layershave different pore sizes and different mass densities. The first layeris the outer selective layer and this layer has the smallest pores andthe highest mass density. The second layer has larger pores and lowermass density than the first layer. The third layer has smaller pores andhigher mass density than the second layer, but has larger pores andlower mass density than the first layer. The fourth layer has largerpores and lower mass density than all of the first, second and thirdlayers. In FIG. 3 c the inner wall surface is shown, and in FIG. 3 d theouter wall surface is shown, the outer wall surface being very smoothand with smooth pores.

The roughness of the outer wall surface was measured and calculated asdisclosed above with a probe having a tip angle of R≈2 nm. For a sampleof the size 2×2 μm, the roughness parameters were R_(a) 3.3 nm and R_(q)4.2 nm, and for a sample of the size 5×5 μm, the roughness parameterswere R_(a) 4.6 nm and R_(q) 5.7 nm.

Example 4

The fourth example has been carried out with the identical compositionof the polymer solution as in Example 1. The viscosity of the polymersolution was 62100 mPa×s.

The polymer preparation procedure was kept as described in Example 1.The membrane formation procedure was changed for the following points:

-   -   Bore liquid (H₂O : NMP) 38 wt.-% : 62 wt.-%    -   Concentration of NMP in the precipitation bath: 69 wt.-%

The remaining process steps are kept as in Example 1. The onlydifference is that the fiber had different dimensions. The hollow fibermembrane has an inner diameter of 311 μm, an outer diameter of 395 μmand a fully asymmetric membrane structure. The active separation layerof the membrane is at the outer wall surface. The active separationlayer is defined as the layer with the smallest pores. The hydraulicpermeability (Lp value) of the membrane is measured from inside tooutside in a hand bundle using the methods described earlier. Themembrane showed a hydraulic permeability of 27.0×10⁻⁴ cm³/(cm² bar sec).

In FIG. 4 a, a scanning electron micrograph of the cross-section of thehollow fiber membrane is shown. In FIG. 4 b a close-up of thecross-section of the hollow fiber wall is shown and, as is evident fromthe picture, the wall has an asymmetric structure and the overallstructure is a sponge-like structure. There are five different layerswithin the hollow fiber wall, and these different layers have beenmarked up, and as could be seen from the picture, the different layershave different pore sizes and different mass densities. The first layeris the outer selective layer and this layer has the smallest pores andthe highest mass density. The second layer has larger pores and lowermass density than the first layer. The third layer has smaller pores andhigher mass density than the second layer, but has larger pores andlower mass density than the first layer. The fourth layer has largerpores and lower mass density than all of the first, second and thirdlayers. The fifth layer has smaller pores and higher mass density thanthe fourth layer. In FIG. 4 c the inner wall surface is shown, and inFIG. 4 d the outer wall surface is shown, the outer wall surface beingvery smooth and with smooth pores.

The roughness of the outer wall surface was measured and calculated asdisclosed above with a probe having a tip angle of R≈2 nm. For a sampleof the size 2×2 μm, the roughness parameters were R_(a) 4.6 nm and R_(q)5.9 nm, and for a sample of the size 5×5 mm, the roughness parameterswere R_(a) 7.2 nm and R_(q) 9.1 nm.

Example 5

The polymer preparation procedure was kept as described in Example 1.The viscosity of the polymer solution was 53560 mPa×s. The membraneformation procedure was changed for the following points:

-   -   Bore liquid (H₂O: NMP) 34 wt.% : wt.-66%    -   Temperature of the spinning nozzle : 60° C.    -   Spinning velocity: 45 m/min    -   Distance between the spinning nozzle and the precipitation bath:        0 cm    -   NMP concentration in the precipitation bath: 62 wt.-%    -   Temperature of the precipitation bath: 25° C.

The remaining process steps are kept as in Example1. The hollow fibermembrane has an inner diameter of 117 μm, an outer diameter of 163 μmand a fully asymmetric membrane structure. The active separation layerof the membrane is at the outer side. The active separation layer isdefined as the layer with the smallest pores. The hydraulic permeability(Lp value) of the membrane is measured from inside to outside in afilter using the methods described earlier. The membrane showed ahydraulic permeability of 13.6×10⁻⁴ cm³/(cm² bar sec).

In FIG. 5 a, a scanning electron micrograph of the cross-section of thehollow fiber membrane is shown. In FIG. 5 b a close up of thecross-section of the hollow fiber wall is shown and, as is evident fromthe picture, the wall has an asymmetric structure and the overallstructure is a sponge-like structure. There are four different layerswithin the hollow fiber wall, and these different layers have beenmarked up, and as could be seen from the picture, the different layershave different pore sizes and different mass densities. The first layeris the outer selective layer and this layer has the smallest pores andthe highest mass density. The second layer has larger pores and lowermass density than the first layer. The third layer has smaller pores andhigher mass density than the second layer, but has larger pores andlower mass density than the first layer. The fourth layer has largerpores and lower mass density than all of the first, second and thirdlayers. In FIG. 5 c the inner wall surface is shown, and in FIG. 5 d theouter wall surface is shown, the outer wall surface being very smoothand with smooth pores.

The roughness of the outer wall surface was measured and calculated asdisclosed above, with a probe having a tip angle of R≈10 nm. For asample of the size 2×2 μm, the roughness parameters were R_(a) 6.8 nmand R_(q) 8.4 nm, and for a sample of the size 5×5 μm, the roughnessparameters were R_(a) 7.3 nm and R_(q) 9.4 nm.

COMPARATIVE EXAMPLE

The first experiment has been carried out with the identical compositionof the polymer solution as in Example 1. The viscosity of the polymersolution was 62100 mPa×s.

The polymer preparation procedure was kept as described in example 1.The membrane formation procedure was changed for the following points:

-   -   Bore liquid (H₂O: NMP) 38 wt.-% : 62 wt.-%    -   Concentration of NMP in the precipitation bath: 72 wt.-%

The remaining process steps are kept as in Example 1. The onlydifference is the point that the fiber had different dimensions. Thehollow fiber membrane has an inner diameter of 312 μm, an outer diameterof 396 μm and a fully asymmetric membrane structure. The hydraulicpermeability (Lp value) of the membrane is measured from inside tooutside in a hand bundle using the methods described earlier. Themembrane showed a hydraulic permeability of 120×10⁻⁴ cm³/(cm² bar sec).

In FIG. 6 a, a scanning electron micrograph of the cross-section of thehollow fiber membrane is shown. In FIG. 6 b a close up of thecross-section of the hollow fiber wall is shown. In FIG. 6 c the innerwail surface is shown, and in FIG. 6 d the outer wall surface is shown.As is evident from FIG. 6 c and FIG. 6 d, the outer wall surface showslarger pores than the inner wall surface. Additionally, the smoothnessof the outer wall surface has decreased and it is rougher.

The roughness of the outer wall surface was measured and calculated asdisclosed above with a probe having a tip angle of R≈10 nm. For a sampleof the size 2×2 μm, the roughness parameters were R_(a) 19.8 nm andR_(q) 26.4 nm, and for a serve of the size 5×5 μm, the roughnessparameters were R_(a) 23.3 nm and R_(q) 30.5 nm, which is clearlyoutside the scope of the present invention.

It should be understood that various changes and modifications to theembodiments described herein, will be apparent to those skilled in theart. Such changes and modifications can be made without departing fromthe spirit and scope of the present invention, and without diminishingits attendant advantages. It is therefore intended that such changes andmodifications be covered by the appended claims.

1-24. (canceled)
 25. A microdialysis device comprising a sensor membranefor direct blood applications, the sensor membrane being a semipermeablehollow fiber membrane comprising an outer wall surface being smooth,continuous, and homogeneous in a nanoscopic scale, an inner wallsurface, and an interior lumen extending along the length of thesemipermeable hollow fiber membrane, the semipermeable hollow fibermembrane having a selective layer on the outer wall surface, the outerwall surface having a smallest pore size and being virtually devoid ofroughness with roughness parameters R_(a) and R_(q) of not more than 10nm, roughness being measured with an atomic force microscope (AFM), andthe roughness parameters R_(a) and R_(q) being calculated using thefollowing equations:$R_{a} = {\frac{1}{N}{\sum\limits_{i = 1}^{N}{Z_{i}}}}$$R_{q} = \sqrt{\frac{1}{N}{\sum\limits_{i = 1}^{N}Z_{i}^{2}}}$ with Nbeing the total number of data points and Z_(i) being the height of adata point above an average picture level.
 26. The device of claim 25,wherein the semipermeable hollow fiber membrane comprises a membranewall having at least four layers with different pore sizes and massdensities, and wherein a layer positioned closest to a middle of themembrane wall has a smaller pore size and a higher mass density than thetwo layers directly adjacent on each side of said layer positionedclosest to the middle of the membrane wall.
 27. The device of claim 25,wherein the semipermeable hollow fiber membrane comprises a membranewall having four layers with different pore sizes and mass densities,and wherein a first layer, at the outer wall surface, has the smallestpore size and the highest mass density, wherein a second layer, adjacentto the first layer, has a larger pore size and lower mass density thanthe first layer, wherein a third layer, adjacent to the second layer,has a smaller pore size and higher mass density than the second layer,but a larger pore size and a lower mass density than the first layer,and a fourth layer, at the inner wall surface and adjacent to the thirdlayer, has a larger pore size and a lower mass density than the first,second, and third layers.
 28. The device of claim 25, wherein thesemipermeable hollow fiber membrane comprises a membrane wall havingfive layers with different pore sizes and mass densities, wherein afirst layer, at the outer wall surface, has the smallest pore size andthe highest mass density, wherein a second layer, adjacent to the firstlayer, has larger pore size and lower mass density than the first layer,wherein a third layer, adjacent to the second layer, has smaller poresize and higher mass density than the second layer, but larger pore sizeand lower mass density than the first layer, a fourth layer, adjacent tothe third layer, has a larger pore size and a lower mass density thanthe first, second and third layers, and a fifth layer, at the inner wallsurface and adjacent to the fourth layer, has a larger pore size and alower mass density than the first, second, third, and fourth layers. 29.The device of claim 25, wherein the semipermeable hollow fiber membranecomprises a membrane wall having five layers with different pore sizesand mass densities, wherein a first layer, at the outer wall surface,has the smallest pore size and the highest mass density, wherein asecond layer, adjacent to the first layer, has larger pore size andlower mass density than the first layer, wherein a third layer, adjacentto the second layer, has smaller pore size and higher mass density thanthe second layer, but larger pore size and lower mass density than thefirst layer, a fourth layer, adjacent to the third layer, has a largerpore size and a lower mass density than the first, second, and thirdlayers, and a fifth layer, at the inner wall surface and adjacent to thefourth layer, has a smaller pore size and a higher mass density than thefourth layer.
 30. The device of claim 25, wherein the semipermeablehollow fiber membrane has a hydraulic permeability within the range of1×10⁻⁴ to 100×10⁻⁴ [cm³/cm²×bar×s].
 31. The device of claim 25, whereinthe semipermeable hollow fiber membrane comprises a polymer compositioncomprising polysulfone (PSU), polyethersulfone (PES) orpolyarylethersulfone (PAES); and polyvinylpyrrolidone (PVP).
 32. Thedevice of claim 31, wherein the polyvinylpyrrolidone (PVP) in thesemipermeable hollow fiber membrane comprises a blend of at least twohomo-polymers of polyvinylpyrrolidone (PVP), and wherein one of thehomo-polymers has an average relative molecular weight within the rangeof 10.000 g/mol to 100.000 g/mol, and another one of the homo-polymershas an average relative molecular weight within the range of 500.000g/mol to 2.000.000 g/mol.
 33. The device of claim 25, wherein thesemipermeable hollow fiber membrane has an inner diameter within therange of 50 to 2000 μm.
 34. The device of claim 25, wherein thesemipermeable hollow fiber membrane has a wall thickness within therange of 10 to 200 μm.
 35. The device of claim 25, wherein thesemipermeable hollow fiber membrane has an effective diffusioncoefficient through the membrane for urea (60 g/mol) within the range of4×10⁻⁶ to 15×10⁻⁶ [cm²/s].